Combined target-based and ligand-based drug design approach as a tool to define a novel 3D-pharmacophore model of human A3 adenosine receptor antagonists: pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as a key study

J Med Chem. 2005 Jan 13;48(1):152-62. doi: 10.1021/jm049662f.


A combined target-based and ligand-based drug design approach has been carried out to define a novel pharmacophore model of the human A(3) receptor antagonists. High throughput molecular docking and comparative molecular field analysis (CoMFA) have been used in tandem to assemble a new target based pharmacophore model. In parallel, to provide more accurate information about the putative binding site of these A(3) inhibitors, a rhodopsin-based model of the human A(3) receptor was built and a novel Y-shape binding motif has been proposed. Docking-based structure superimposition has been used to perform a quantitative study of the structure-activity relationships for binding of these pyrazolo-triazolo-pyrimidines to adenosine A(3) receptor using CoMFA. Both steric and the electrostatic contour plots obtained from the CoMFA analysis nicely fit on the hypothetical binding site obtained by molecular docking. On the basis of the combined hypothesis, we have designed, synthesized, and tested 17 new derivatives. Consistently, the predicted K(i) values were very close to the experimental values.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A3 Receptor Antagonists*
  • Animals
  • Binding Sites
  • Combinatorial Chemistry Techniques
  • Cricetinae
  • Drug Design
  • Drug Evaluation, Preclinical
  • Humans
  • Ligands
  • Models, Molecular*
  • Models, Theoretical
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Quantitative Structure-Activity Relationship*
  • Receptor, Adenosine A3 / chemistry
  • Receptor, Adenosine A3 / metabolism
  • Reproducibility of Results
  • Rhodopsin / chemistry
  • Rhodopsin / metabolism
  • Static Electricity
  • Triazoles / chemistry*


  • Adenosine A3 Receptor Antagonists
  • Ligands
  • Pyrazolotriazolopyrimidine
  • Pyrimidines
  • Receptor, Adenosine A3
  • Triazoles
  • Rhodopsin